Project Summary/Abstract Obesity has reached epidemic proportions and is a risk factor for fractures in both children and adults, despite higher DXA measures of areal bone mineral density (BMD). Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are bariatric procedures that are increasingly used in adolescents. However, studies in adults suggest that accelerated bone loss may be a major metabolic complication of bariatric surgery. This is of particular concern during adolescence, a time of maximal bone accrual towards attainment of peak bone mass, a key determinant of future fracture risk. Although bariatric surgery in obese adolescents is becoming increasingly common, there is a major knowledge gap regarding consequences on bone in adolescents with commonly used bariatric procedures. Of note, the use of DXA in obesity and following weight loss is prone to artifactual inaccuracies and may not reflect true changes in bone strength. In contrast, quantitative computed tomography (QCT) and high-resolution peripheral QCT (HR-pQCT) avoid many limitations of DXA, and may yield critical insight about structural changes, and microfinite element analysis (?FEA) provides non-invasive strength estimates. These methods have not been utilized to characterize bone changes in adolescents undergoing bariatric surgery. Recent developments have brought to light the bone-fat connection and the potential impact of marrow adipose tissue (MAT) in the pathogenesis of osteoporosis. However, the impact of bariatric surgery on MAT (measured in vivo using magnetic resonance spectroscopy (1H-MRS)) has not been studied in adolescents. Finally, an understanding of mechanisms that impact bone metabolism after RYGB and VSG could inform future therapies, and is lacking in adolescents. Our overall goal is to comprehensively evaluate skeletal health over 2 years in morbidly obese adolescents undergoing RYGB and VSG compared with matched non-surgical obese controls (Aim 1), and investigate mechanisms that contribute to deleterious changes in bone metabolism following bariatric surgery (Aim 2). Bone density will be assessed at the spine and hip by DXA and quantitative CT (QCT), and the whole body by DXA, before and for 2 years after RYGB and VSG, compared to matched non-surgical obese controls. We will evaluate biochemical markers of bone turnover and changes in bone microarchitecture at the radius and tibia (using HRpQCT) to ascertain how alterations in bone re/modeling and microarchitecture impact bone, and the implication of these changes for fracture risk by assessing changes in strength estimates (using ?FEA). Marrow fat will be assessed using1H- MRS. Finally, we will evaluate complex interactions between bone, body composition and hormones that change with RYGB and VSG (insulin, ghrelin, peptide YY, estrogen) and may affect bone directly or via hormones such as sclerostin and Pref-1. We have assembled investigators with complimentary strengths for the proposal.